Which Grandparent Are You Most Related to?

What makes you who you are genetically? The easy answer is your family. The longer answer begins with the fact that all humans have two parents (at least for now), and usually four distinct grandparents (there are unfortunate exceptions). Genetically you are a recombination of four separate individuals. But that does not mean you have an equal contribution from four separate individuals. Humans normally carry 23 pairs of chromosomes: 22 autosomal pairs and one pair of sex chromosomes, either two copies of the X for a female or an X and a Y in the case of males. By Mendel’s law of segregation you receive one copy of each pair from your mother (via the egg), and one copy from your father (via the sperm). This means exactly half of your genome derives from each parent.

Things begin to get more complicated going back two generations. One might think that of the 44 autosomal chromosomes you would receive 11 from each of the four grandparents. (For simplicity we’ll leave the sex chromosomes out for now. If you are a female, you receive one X from each parent, while if you are a male you receive an X from your mother and a Y from your father, who got it from his father.) But while the proportion of one’s inheritance from parents is fixed by exact necessity, the fraction from grandparents is governed by chance. For each of the chromosomes you inherit from a given parent, you have a 50 percent chance of gaining a copy from your grandfather and a 50 percent chance of gaining a copy from your grandmother. The laws of independent probability imply that there is a 1 in 4 million chance that all of your maternal or paternal chromosomes could come from just one grandparent!* What’s more, genetic recombination means that chromosomes aren’t purely from one grandparent or the other; during the cell divisions that produce sperm and eggs, chromosomes exchange segments and become hybrids. You almost certainly have different genetic contributions from your four grandparents.

But this is not just abstract theorizing. Imagine that you could know that 22 percent of the genome of your child derives from your mother, and 28 percent from your father. Also imagine that you know that 23 percent of the genome of your child derives from your partner’s mother, and 27 percent derives from your partner’s father. And you could know exactly how closely your child is related to each of its uncles and aunts. This isn’t imaginary science fiction, it is science fact.

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Last year, I sent a sample of my then 2-month-old daughter’s genetic material to the firm 23andMe and received her results. As it happens I already had the genotype of my daughter’s mother, father, all her uncles and aunts, and all four of her grandparents. In other words, her full pedigree was already available when her results came back, and she was easily slotted into the bigger genomic family photo album. Not only do I know which proportions of her ancestry derived from each grandparent, I know which regions of her genome derive from each of her grandparents. For example, one grandmother is half Norwegian, so genealogically my daughter isone-eighth Norwegian. But I quickly calculated using diverse data sets of various nationalities that genomically she is somewhat more than one-eighth Norwegian. This is reasonable as 28 percent of her ancestry, according to how her DNA analysis matches up with the DNA of the rest of the family, happens to come from her half Norwegian grandmother.

One might think these sorts of facts are useful only for the sake of satisfying curiosity, but sometimes theoretical knowledge can be put to practical use. Last spring my wife asked our pediatrician about testing my daughter for a treatable autosomal dominant condition which I happen to exhibit. The physician’s reaction was straightforwardly paternalistic. She would not authorize the test because she believed our daughter was too young. This did not sit well with my wife. The mutated gene which causes my condition has been well characterized. My wife went home and quickly used one of 23andMe’s features to find out if my daughter inherited a copy of the gene through me from my mother or my father. My mother is affected by the same ailment as I am, while my father is not. The happy ending is that my daughter almost certainly does not have the condition, because she inherited that genetic region from my father. The bigger moral of the story is that decentralized genetic information can allow persistence to pay off.

All of this is a consequence of the fact that I have an obsession with genetics. But it is also contingent on the fact that for less than $500, you can send in a kit and receive back a record of 1 million genetic variants in short order. This would have been unfathomable just 10 years ago. Out of 3 billion base pairs in the entire human genome, 1 million may not seem like much, but the ones tested were chosen because they vary across the population, and they represent a substantial proportion of the variable genome. Much of the information is banal, trivial, and redundant. My eyes are dark brown, and those of my wife are blue. Therefore, you will not be surprised to learn that a quick check on variants that code for eye color predicts that my daughter will shake out to have a light brown shade (as a matter of fact her eyes are light brown or hazel).

Other results are more relevant. I am a “PTC nontaster.” This means that I lack the ability to perceive a particular chemical called phenylthiocarbamide, which is often applied to paper one can touch to the tongue in high school biology classes to illustrate genetic inheritance of recessive traits. My wife has a copy of the tasting variant, as well as the nontasting one. (Her father, a notoriously finicky eater, has two copies of the tasting variant, and so he is a “super-taster.”) In real world terms it means that my wife has a greater sensitivity to bitter foods than I do, something I can attest to as a real phenomenon. For me, salad dressing is optional. There are studies which suggest that small children who are tasters tend to be fussy eaters, as opposed to those who are nontasters. You can guess which result I was rooting for. And in this case the die landed exactly as I would have preferred: My daughter is a nontaster, just like her father!

At this point you may wonder if my daughter’s future, in my mind, is predicted down to minute details by the character of her genotype. No. The reality is that most heritable traits are difficult to predict from specific genes because they are influenced by so many genes. (This is why I was so interested in which grandparents she received more of her genes from overall, by the way.) When it comes to individual prediction, most of the strongly predictive genes influence traits we already can see with our eyes. (My daughter will have wet earwax!) But even facts which might seem silly can loom large for grandparents. To my mother’s chagrin, my father is quite proud of his disproportionate contribution to his granddaughter. Similarly, it is clear my mother-in-law has no complaints about being overrepresented in the genetic constitution of her first grandchild.

My daughter is a nontaster, just like her father!

But the story does not end here. Let’s shift from science fact to science fiction. A survey of 1 million variants of a 2-month-old are to a great extent for entertainment purposes only, as the promotional material for 23andMe cautions. But in the very near future, parents will be able to avail themselves of precise and accurate genomes of their future childin utero. Potential sperm donor clients will be able to simulate thousands of potential offspring outcomes from different male contributors. Currently, only primitive assays are available in utero, such as whether your child has a chromosomal abnormality which might indicate Down syndrome. But imagine a scenario in which parents are given a summary from their genetic analyst of their future child at the sixth week of pregnancy. That summary will include superficial characteristics, perhaps even predictions of facial morphology. But it will also have a number that indicates mutational load for large-impact genes. This number will vary from fetus to fetus. Mutation is after all somewhat random.

The implications are obvious. Go with a child with a higher mutational load than you prefer? Or try again? This will be especially important for the children of older fathers, who are already contributing more than their share to the mutations in their offspring. Accuracy is of the essence for what comes next. The personal genetics tests available today look for common variations within the population. One of the possible “killer apps” of genomics in the near future may be to assess the regions of the genome where an individual has unique mutations, ones that differ from the parents’ DNA. These variants are informative in a way that family history simply can’t be.

When it comes to personal genomics, we currently live in the age of the hobbyist. There are a plethora of websites that can do genealogical analysis for you if you don’t have computational skills. Off the shelf applications give you updates on the latest research on a particular variant of personal interest. I hope in the near future I can install a smartphone app that feeds me a stream of actionable results. Personal genomics is truly leveraged once you integrate it holistically into the quantified-self framework. Not only would you know the genome you were born with, but you could have hourly updates on biomarker results, as well your continuous pace of physical activity. Disease risk in many cases is a combination of both genes and environment, and integrating information from both domains opens up many possibilities. Naturally there are people in Silicon Valley working on projects which aim to take this framework to the mass market.

The goal here is not to foresee my daughter’s destiny, it is to understand it and shape it so that she can flourish. I take a mild interest in my own genomics, but I am surprised at how much more interested I am in my daughter’s results. For her the future will be. Much of my future has been determined by choices made in the pre-genomic era. By the time she is entering elementary school I expect to have a full and accurate copy of her whole genome. At that point we’ll start a new discussion about who she is, and who she wants to be. I’m a geneticist, not a developmental psychologist, so this is going to be an experiment where I am totally at a loss for forecasting the outcome. But someone has to step out of the cave of personal genomic ignorance first, and see if the coast is clear.

*Correction, Oct. 18, 2013: This article originaly misstated the odds that the chromosomes from one parent could come entirely from just one grandparent.There is a 1 in 4 million chance of this happening.

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